A multifunctional hyaluronic acid hydrogel with pH-responsive metformin release for accelerated healing of diabetic...

Diabetic wounds remain a global public-health threat due to simultaneous bleeding, bacterial colonization and persistent inflammation. We hypothesized that a dynamic metal-polyphenol hydrogel that instantly seals bleeding vessels, acid-triggered releases metformin and synergistically photothermal antibacterial would break this deadlock. Therefore, we developed a multifunctional hyaluronic acid hydrogel (ODF-Met) by conjugating metformin to dopamine-grafted oxidized hyaluronic acid via dynamic imine bonds, followed by coordination with Fe³⁺ to form a dynamic metal-polyphenol network. This unique structure endows ODF-Met with remarkable photothermal antibacterial efficacy (≈100 %), self-healing ability, biodegradability and robust tissue adhesion (30 kPa). Importantly, ODF-Met exhibits smart pH-responsive release behavior, with cumulative release rates of 87.9 ± 6.8 % (pH = 5.5) within 3 h and 85.0 ± 4.0 % (pH = 7.4) within 60 h. The acid-triggered metformin release significantly enhanced intracellular ROS scavenging and promoted endothelial cell angiogenesis, thereby amplifying the therapeutic effects of metformin. Unlike traditional sustained-release systems based on covalent conjugation, microspheres, or micelles, the combination of dynamic imine and metal-polyphenol bonds ensures controlled, pH-triggered drug release while preserving metformin bioactivity. The experiments validated that ODF-Met achieved rapid hemostasis (<10 s), exerted potent photothermal antibacterial action and synergistically provided anti-inflammatory, antioxidant and angiogenic effects. It successfully promoted scarless healing of diabetic infected wounds. In conclusion, ODF-Met represents an integrated and innovative strategy for diabetic wound repair, offering a new design paradigm for metformin delivery systems aimed at achieving tissue regeneration without scarring.